Defining the role of glucocorticoid-related dendritic spine plasticity in cocaine-induced habits

项目摘要 目标导向行动是指根据预期结果选择行动的能力。与目标相反- 定向行动，习惯是刺激引起的，对目标不敏感。目标导向的行为和习惯都是 习惯对生存很重要，但习惯可能是适应不良的，是许多神经精神疾病的特征。 可卡因使用障碍（CUD）第一份报告说，可卡因造成的偏见，以习惯为代价， 啮齿类动物目标导向行为的研究发表于15年前，但其潜在机制仍不清楚。 可卡因会导致应激激素的释放，可卡因和应激激素都会导致 眶额皮质（OFC）中树突棘的不稳定。对啮齿动物的研究也表明， 输注使眶额皮层树突棘不稳定的药物会破坏目标导向的行为，导致对目标的偏好。 习惯性行为研究者将检验长期接触可卡因导致习惯的假设 通过增加循环应激激素水平，激活糖皮质激素受体（GR）， 导致眶额皮层树突棘缺失。因此，研究人员将确定可卡因 导致习惯偏见。 在目标1中，研究者将使用体内病毒介导的基因沉默和称为“工具沉默”的任务。 应急退化”，它测试小鼠将训练的反应与其可能的结果联系起来的能力。 研究者将由此确定可卡因是否会降低目标导向行为（导致习惯偏差） 通过长时间刺激眶额皮层的GR研究人员假设长期接触可卡因 通过触发CORT释放诱导习惯，引起OFC中GR的慢性激活。因此，减少GR OFC中的水平将防止可卡因引起的习惯性行为。 在目标2中，研究者将使用药理学技术直接操纵肌动蛋白细胞骨架 选择性地在OFC内，以确定细胞骨架稳定性在OFC依赖的目标导向作用中的作用。 研究者假设，刺激树突棘发生将促进目标导向的行动， 可卡因暴露的小鼠，而不稳定的树突棘将阻止这种作用。 普遍认为精神兴奋剂和应激改变树突和树突棘密度， 形态，但与滥用药物或压力源的行为影响的因果关系基本上没有 验证因此，通过开展这项拟议的工作，调查人员将解决基本的悬而未决的问题， 关于应激激素和树突棘可塑性如何影响可卡因的方式的问题 改变复杂的决策。这项研究是高度转化的，可以揭示新的治疗方法。 CUD，目前没有药物治疗，同时也使研究人员具备技能， 这是一个成功的科学生涯所必需的。

Project Summary Goal-directed action refers to the ability to select an action based on a desired outcome. In contrast to goal- directed actions, habits are stimulus-elicited and insensitive to goals. Both goal-directed action and habits are important for survival, but habits can be maladaptive and are characteristic of many neuropsychiatric diseases including cocaine use disorder (CUD). The first report that cocaine causes a bias towards habits at the expense of goal-directed action in rodents was published ~15 years ago, but the underlying mechanisms remain unclear. Cocaine causes the release of stress hormones, and both cocaine and stress hormone exposure cause the destabilization of dendritic spines in the orbitofrontal cortex (OFC). Research in rodents also indicates that local infusion of drugs that destabilize dendritic spines in the OFC disrupts goal-directed action, causing a bias towards habitual behavior. The investigator will test the hypothesis that chronic cocaine exposure causes habit biases by increasing levels of circulating stress hormones, activating glucocorticoid receptors (GR), leading to dendritic spine loss in the OFC. The investigator will thus identify mechanisms by which cocaine induces habit biases. In Aim 1, the investigator will use in vivo viral-mediated gene silencing and a task termed “instrumental contingency degradation”, which tests the ability of mice to associate a trained response with its likely outcome. The investigator will thereby determine whether cocaine degrades goal-directed action (causing habit biases) via prolonged stimulation of GRs in the OFC. The investigator hypothesizes that prolonged cocaine exposure induces habits by triggering CORT release, causing chronic activation of GRs in the OFC. Thus, reducing GR levels in the OFC will protect against cocaine-induced habitual behavior. In Aim 2, the investigator will use pharmacological techniques to directly manipulate the actin cytoskeleton selectively within the OFC to determine the role of cytoskeletal stability in OFC-dependent goal-directed action. The investigator hypothesizes that stimulating dendritic spinogenesis will promote goal-directed action in cocaine-exposed mice, while destabilizing dendritic spines will block this effect. It is widely accepted that psychostimulants and stress modify dendrite and dendritic spine densities and morphologies, yet causal relationships with the behavioral effects of drugs of abuse or stressors are largely not verified. Thus, by carrying out this proposed work, the investigator will address fundamental unanswered questions regarding how stress hormones and dendritic spine plasticity influence the manner in which cocaine alters complex decision making. This research is highly translational and could reveal new approaches to treating CUD, for which no pharmacotherapies currently exist, while also equipping the investigator with the skills necessary for a successful scientific career.